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Evolution of visual acuity in the treated eye vs. untreated eye over 2.5 years of follow up, in subjects with less than 2 years of vision loss and visual acuity < 2.79 LogMAR at baseline* - * Excludes "hand motion" patients, in accordance with the Phase III protocol. Credit photo: Gensight Biologics

Evolution of visual acuity in the treated eye vs. untreated eye over 2.5 years of follow up, in subjects with less than 2 years of vision loss and visual acuity < 2.79 LogMAR at baseline* - * Excludes "hand motion" patients, in accordance with the Phase III protocol. Credit photo: Gensight Biologics

GenSight Biologics (Paris: SIGHT) (Euronext: SIGHT, ISIN: FR0013183985,
PEA-PME eligible), a biopharma company focused on discovering and
developing innovative gene therapies for neurodegenerative retinal
diseases and diseases of the central nervous system, today reported 2.5
years of follow-up data from its Phase I/II clinical trial with the
Company’s gene therapy GS010 in patients with Leber Hereditary Optic
Neuropathy (LHON). These results confirm long-term sustained gains in
visual acuity 2.5 years after a single intravitreal injection of GS010,
especially in subjects with less than 2 years of onset of vision loss.

In the study, five cohorts of three subjects were administered an
increasing dose of GS010 via a single intravitreal injection in the eye
more severely affected by the disease. Recruitment of 15 subjects was
completed in April 2015 and long-term follow-up is ongoing. Subjects had
an average onset of vision loss of 6 years at the time of treatment. At
baseline, both treated (TE) and untreated (UTE) eyes had an off-chart
median visual acuity.1

At year 2.5 post-injection, in subjects less than 2 years from
onset of vision loss and with relatively better vision at the time of
treatment (<2.79 LogMAR),2 TE had a mean gain of +28
ETDRS letters (-0.55 LogMAR) compared to baseline, while UTE
had a mean gain of +13 ETDRS letters (-0.25 LogMAR) compared
to baseline. The difference of +15 ETDRS letters in favor of TE is
clinically significant, and the magnitude of the improvement, which
is similar to the trend observed at Weeks 48, 78, and 96, suggests
sustained benefit from GS010.

The subject group (n=5) with an onset of vision loss of less than 2
years and relatively better vision at the time of injection (<2.79
LogMAR) demonstrated a sustained pharmacological trend in favor of the
treated eye, of increasing magnitude from Week 36 onwards, with 60%
of subjects showing a clinically significant gain of ≥ 15 letters in TE
at year 2.5.3 The characteristics of this subject group are
similar to the baseline characteristics of LHON patients enrolled in
ongoing Phase III REVERSE and RESCUE clinical trials4.

In all subjects (n=14), the mean change from baseline of visual acuity
in TE showed an improvement of +29 ETDRS letters (-0.58 LogMAR) that was
both clinically and statistically significant (p = 0.0034), while the
mean change in UTE from baseline of visual acuity showed an improvement
of +22 ETDRS letters (-0.44 LogMAR), which was not statistically
significant. The difference of +7 ETDRS letters was in favor of TE.

3 Clinical significance is defined as a change from baseline
of at least -0.3 LogMAR (≥ +15 ETDRS letters)4 One
patient had vision loss for 9 months at treatment administration
(eligible to REVERSE, 6 to 12 months after onset), and 4 patients had a
duration of vision loss > 1 year and < 2 years. None would have been
eligible to RESCUE (< 6 months after onset).

Bernard Gilly, CEO and co-founder of GenSight, commented, “Not
only do we see a significant clinical benefit in recently diagnosed
subjects, but this benefit is sustained after 2.5 years with a single
injection of GS010. This is particularly encouraging, as we are now less
than 6 months away from Phase III efficacy data with RESCUE and REVERSE.”

Dr. Catherine Vignal, investigator of the study and Chief of the
Department of Ophthalmology at the Rothschild Foundation Hospital in
Paris, added, "The confirmatory safety and continued positive trends
after 2.5 years of follow-up constitute significant hope for patients
suffering from LHON. It is worth noting that the observed improvement in
some of the untreated eyes was consistent with several prior studies in
neuroretinal degenerative diseases. The insights gained from this and
forthcoming data will be tremendously helpful, as GenSight works to
develop a therapy for this severe blinding disease affecting patients in
the prime of their life, and for which no curative treatment exists.”

GenSight Biologics is currently conducting two Phase III clinical
studies (RESCUE and REVERSE) in Europe and the United States to assess
the efficacy of GS010 in subjects affected with LHON due to the ND4
mutation, and with vision loss up to one year at the time of treatment.
Recruitment of REVERSE was completed in February 2017, and RESCUE was
completed in August 2017. Topline results at 48 weeks for REVERSE and
RESCUE are expected in the second and third quarters of 2018,
respectively.

About GenSight Biologics

GenSight Biologics S.A. is a clinical-stage biopharma company focused on
discovering and developing innovative gene therapies for
neurodegenerative retinal diseases and diseases of the central nervous
system. GenSight Biologics’ pipeline leverages two core technology
platforms, the Mitochondrial Targeting Sequence (MTS) and optogenetics
for retinitis pigmentosa, to help preserve or restore vision in patients
suffering from severe degenerative retinal diseases. GenSight Biologics’
lead product candidate, GS010, is in Phase III trials in Leber
Hereditary Optic Neuropathy (LHON), a rare mitochondrial disease that
leads to irreversible low vision and legal blindness in teens and young
adults. Using its gene therapy-based approach, GenSight Biologics’
product candidates are designed to be administered in a single treatment
to each eye by intravitreal injection to offer patients a sustainable
functional visual recovery.

About GS010

GS010 targets Leber Hereditary Optic Neuropathy (LHON) by leveraging a
mitochondrial targeting sequence (MTS) proprietary technology platform,
arising from research works conducted at the Institut de la Vision
in Paris, which, when associated with the gene of interest, allows the
platform to specifically address defects inside the mitochondria using
an AAV vector (Adeno-Associated Virus). The gene of interest is
transferred into the cell to be expressed and produces the functional
protein, which will then be shuttled to the mitochondria through
specific nucleotidic sequences in order to restore the missing or
deficient mitochondrial function.

About Leber Hereditary Optic Neuropathy (LHON)

Leber Hereditary Optic Neuropathy (LHON) is a rare maternally inherited
mitochondrial genetic disease, characterized by the degeneration of
retinal ganglion cells that results in brutal and irreversible vision
loss that can lead to legal blindness, and mainly affects adolescents
and young adults. LHON is associated with painless, sudden loss of
central vision in the 1st eye, with the 2nd eye
sequentially impaired. It is a symmetric disease with poor functional
visual recovery. 97% of patients have bilateral involvement at less than
one year of onset of vision loss, and in 25% of cases, vision loss
occurs in both eyes simultaneously. The estimated incidence of LHON is
approximately 1,400 to 1,500 new patients who lose their sight every
year in the United States and Europe.

About RESCUE and REVERSE

RESCUE and REVERSE are two separate randomized, double-masked,
sham-controlled pivotal Phase III trials designed to evaluate the
efficacy of a single intravitreal injection of GS010 (rAAV2/2-ND4) in
subjects affected by LHON due to the G11778A mutation in the
mitochondrial ND4 gene.

The primary endpoint will measure the difference in efficacy of GS010 in
treated eyes compared to sham-treated eyes based on Best Corrected
Visual Acuity (BCVA), as measured with the ETDRS at 48 weeks
post-injection. The patients’ LogMAR (Logarithm of the Minimal Angle of
Resolution) scores, which are derived from the number of letters
patients read on the ETDRS chart, will be used for statistical purposes.
Both trials have been adequately powered to evaluate a clinically
relevant difference of at least 15 ETDRS letters between treated and
untreated eyes adjusted to baseline.

The secondary endpoints will involve the application of the primary
analysis to best seeing eyes that received GS010 compared to those
receiving sham, and to worse seeing eyes that received GS010 compared to
those that received sham. Additionally, a categorical evaluation with a
responder analysis will be evaluated, including the proportion of
patients who maintain vision (< ETDRS 15L loss), the proportion of
patients who gain 15 ETDRS letters from baseline and the proportion of
patients with Snellen acuity of >20/200. Complementary vision metrics
will include automated visual fields, optical coherence tomography, and
color and contrast sensitivity, in addition to quality of life scales,
bio-dissemination and the time course of immune response.

The trials are conducted in parallel, in 37 subjects for REVERSE and 39
subjects for RESCUE, in 7 centers across the United States, the UK,
France, Germany and Italy. Topline results of REVERSE at 48 weeks are
expected in Q2 2018, while RESCUE is expected to read out in Q3 2018.